8h-isoquino(1,2-b)quinazolin-8-ones



United States Patent Int. Cl. C07d 51/48 US. Cl. 260-251 9 Claims ABSTRACT OF THE DISCLOSURE Compounds from the group consisting of 5,6-dihydro- 5,6,13,13a tetrahydro-, and 5,6,8a,9,10,1l,12,l2a,13, l3a-decahydro 8H isoquino[1,2-b]-quinazolin-8-ones. The compounds are useful as central nervous system depressants, antiinfiammatories and antipyretic agents.

This application is a division application of Ser. No. 623,238 filed Mar. 15, 1967 now Pat. No. 3,497,499, issued Feb. 24, 1970.

This invention relates to the compounds of the formula:

Intermediates of Compounds I include compounds of the formulae:

Bi R

R II

wherein R R R A A and ring A are as defined below;

1 III 3,530,129 Patented Sept. 22, 1970 ice wherein R R R ring A, A and A are as defined below, and

wherein:

, Ring A is a member selected from the group consisting of ortho-phenylene and orthocyclohexylene;

R is a member selected from the group consisting of a hydrogen atom, linear alkyl having from 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl and butyl, linear alkoxy having from 1 to 4 carbon atoms, e.g. methoxy, ethoxypropoxy and butoxy and, taken together with R methylenedioxy (OCH -O);

R is a member selected from the group consisting of a hydrogen atom, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with R methylenedioxy;

R is a member selected from the group consisting of a hydrogen atom and methyl;

R is a linear alkyl having from 1 to 4 carbon atoms;

A is a member selected from the group consisting of a hydrogen atom, fluoro, chloro, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with A methylenedioxy;

A is a member selected from the group consisting of a hydrogen atom, fluoro, chloro, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with A methylenedioxy;

B is a member selected from the group consisting of a hydrogen atom, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with B methylenedioxy;

B is a member selected from the group consisting of a hydrogen atom, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with B methylenedioxy; and

X is a member selected from the group consisting of chloro, bromo and iodo, provided "that each of A A B and B is ahydrogen atom where Ring A is orthocyclohexylene:

Compounds I include the classes of compounds Ia; Ib; 1c and Id:

E E Ia wherein R R, A and A are as defined above.

and

a G d m m m 1 m m m m ,wm 0 c m H H m m e w m l S A n n mm B N N N m N I II A V N re A V N V P A P we H H H AM H C O dd nn w m mam mm 3.1.. m R Aww 2 d mm Rmnc as h w W 0 5 0 5 0 rd 0 5 0 5 2 2 3 0O 4 4 5 5 6 6 m w m m m I e a u m d mm a 3 d M M H f O O O O a T n TOY N .H T 4\ N x N N N N 3 L A A V Mm H O H w d Q m n u B 1 z 2 Q mm m m R w R R R R m m n.. Rwm n mm umw h C w H IVa According to the reaction scheme, step a is a condensation of a dihydroisoquinoline (V) with an isatoic anhydride (VI), e.g. by admixing and heating compounds V and VI, to form a compound II (a isoquino[1,2-b] quinazolin-8-one.)

Step b is a reduction of the compound II to the corresponding compound III, e.g. by heating with lithium aluminum hydride (LAH) in a suitable solvent, e.g. di ethyl ether (ether).

Step 0 is a conversion of the compound III to a compound IV, i.e. its corresponding quaternary ammonium salt, by treatment, with R X, i.e. a lower alkyl halide, e.g. CH I in ether.

In step d the compound IV is reduced with sodium in liquid ammonia to the corresponding compound I. It is noted that where A or A of the compound IV is a hydrogen atom, alkyl, alkoxy or a methylenedioxy then upon reduction, the B and B substituents of the resulting compound I, correspond to A and A of compound =IV. However, if any of A and A of compound IV is halo, i.e. fiuoro or chloro, then such halo is converted to a hydrogen in step d. Hence, where any of A and A is halo, then corresponding B or B of the resulting compound I, will be a hydrogen. It is preferred to use compounds IV wherein A and A correspond to the desired B and B substituents of the compound I.

Since step a of the reaction scheme is an idealized illustration, it shows the preparation of compounds II. However, it has been found that in carrying out step a that where R is a hydrogen atom, compounds VII, are also formed, i.e. compounds of the formula:

VII

wherein R R A A and ring A are as defined above.

Subjection of a compound IIIa or 1110 to a hydrogen atmosphere, e.g. 20 to psi, in the presence of PtO preferably in a solvent, e.g. ethanol, with agitation, results in the preparation of a compound VIII, i.e. a compound of the formula:

R1 q R N VIII A1 wherein R ,R A A and ring A are as defined above.

Compounds 11a, 11b, IIc and 11d may be prepared according to the reaction scheme by using as compound VI an isotoic anhydride, an N-methyl isotoic anhydride, hexahydroisotoic anhydride and N-methyl hexahydroisotoic anhydride, respectively.

Compounds 11a and 11b can be converted to compounds I10 and 11d, respectively, by hydrogenation by well-known methods. Where any of A or A of compounds Ila or 11b is halo then such halo is converted to a hydrogen atom during the hydrogenation. Example 9, presented hereinafter, illustrates such a conversion.

Compounds I, II, III, VII and VIII are active upon the central nervous system. Compounds I are useful as central nervous system stimulants and also hypotensive agents. They may be administered to mammals either orally or parenterally in daily doses of from 1 to 10 mg./kg. of body weight, e.g., from 50 to 600 mg. per diem, preferably administered in divided doses from 2 to 4 times a day.

Compounds II, III, VII and VIII are useful as central nervous system depressants, anti-inflammatories and anti pyretics. They are administered to mammals either orally or parenterally in daily doses of from 5 to 30 mg./kg. of body weight, e.g., from 300 to 1800 milligrams per diem, preferably administered in divided doses 2 to 4 times a day.

Pharmaceutically acceptable acid addition and quaternary ammonium salts of compounds I, III and VIII are equally as effective as compounds I, III and VIII, respectively and may be used in a similar manner. The acid addition and quaternary ammonium salts may be prepared according to well-known procedures from com pounds I, III and VIII, respectively. They are all useful, in accord with recognized procedures, for the preparation of corresponding pharmaceutically acceptable salts.

Among the pharmaceutically acceptable acid addition salts are salts of organic acids, e.g. tartaric acid; inorganic acids, e.g. hydrochloric acid, hydrobromic acid and sulfuric acid; monobasic acids, e.g. an alkylsulfonic acid, such as methylsulfonic acid (H CSO H) dibasic acids, e.g. succinic acid; tribasic acids, e.g. phosphoric acid and citric acid; saturated acids, e.g. acetic acid; ethylenically unsaturated acids, e.g. maleic acid and fumaric acid; and aromatic acids, e.g. salicylic acid and arylsulfonic acids, such as phenylsulfonic acid. The only limitation on the acid is that the resulting salt be pharmaceutically acceptable; it is preferred, however, that the acid addition salt be water-soluble.

Each of the pharmaceutically active compounds of this invention may be, e.g. incorporated, for oral administration, in a tablet as the sole active ingredient. A typical tablet is constituted by from 1 to 3 percent binder, e.g. tragacanth; from 3 to percent disintegrating agent, e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum; from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an average dosage of active ingredient; and q.s. 100 percent of filler, e.g. lactose; all percentages being by weight. Tablets are prepared according to standard tabletting techniques, which are well-known in the art, employing the necessary amounts of conventional granulating liquids, e.g. alcohol SD-30 and purified water. An exemplary tabletting formulation for the instant active Examples illustrative of this invention follow. In the example all temperatures are in degrees centigrade and all percents and parts are by weight, unless specified otherwise. Parts by weight are related to parts by volume as a kilogram is related to a liter.

8 EXAMPLE 1 2,3-dimethoxy-5,6,13,13a-tetrahydro-SH-isoquino- [1,2-b] quinazolin-fS-one orno q 01130 N Y H-N This example illustrates the preparation of a compound II according to step a of the reaction scheme presented above. The title compound is useful as a starting material for preparing compounds III, IV and I as is illustrated in Examples 2, 3 and 4, respectively.

Heat under reflux a mixture of 6 parts of 6,7-dimethoxy-3,4-dihydroisoquinoline and 5.1 parts of isatoic anhydride in 60 parts by volume of toluene under nitrogen for 16 hours. Cool the mixture, collect the resultant crystalline precipitate and recrystallize from methanol to obtain the title compound, M.P. 164 to 168 C.

Replacing the 6,7-dimethoxy-3,4-dihydroisoquinoline with 6,7 methylenedioxy 3,4 dihydroisoquinoline results, in a similar manner, of the corresponding compound II.

EXAMPLE 2 CHaO This example illustrates the preparation of a compound III which is useful in preparing compounds IV, as is illustrated in Example 3.

Add 45 parts of 2,3-dimethoxy-5,6,l3,13a-tetrahydro- 8H-isoquino[1,2-b]quinazolin-8-one suspended in 1500 parts by volume of tetrahydrofuran (THF) to a solution of 14 parts of lithium aluminum hydride (LAH) in 1300 parts by volume of ether and heat under reflux for 40 hours. Cool the reaction mixture, wash with parts by volume of water and filter. Evaporate the filtrate under vacuum to obtain a residue Which is then crystallized from ether to obtain the title compounds, M.P. 170 to 172.

Replace the 2,3-dimethoxy-5,6,13,13a-tetrahydro-8H- isoquino[1,2-b]quinazolin-8-one with 5,6,8a,9,10,l1,12, 12a,13,13a-decahydroisoquino[1,2 b]quinazo1in 8 one results in the preparation, in a similar manner of the corresponding compound III.

EXAMPLE 3 2,3-dimethoxy-5,6,13 ,13a-tetrahydro-8H-isoquino- 1,2-b] quinazoline methiodide q omr c1130 F IEI-N This example illustrates the preparation of the title compound which is a compound IV which is useful for preparing a compound I as is illustrated in Example 4.

Prepare a solution of 1 part 2,3-dimethoxy-5,6,l3,13atetrahydro-8H-isoquino[1,2-b]quinazoline in 7 parts by volume of CH Cl 3 parts by volume of ether and 3 parts by volume of methyl iodide and allow the solution to stand at room temperature (20 C.) for /2 hour. Evaporate the solution to dryness under vacuum and recrystallize the residue from ethanol to obtain the title compound, M.P. 245 to 250 C.

Replacing the methyl iodide with ethyl bromide results in the preparation, in a similar manner, of the corresponding compound IV.

EXAMPLE 4 CHsO This example illustrates the preparation of a compound I.

Add one part of sodium to a stirred suspension of 4 parts of 2,3-dimethoxy-5,6,l3,l3a-tetrahydro-8H-isoquino- [1,2-b]quinazoline methiodide in 100 parts by volume of liquid ammonia cooled in a solid carbon dioxide-acetone bath. Stir for one hour then allow the mixture to evaporate for 16 hours. Add water to the residue and extract with chloroform. Dry the chloroform extracts over sodium sulfate and evaporate under vacuum. Crystallize the residue from ether to obtain the title compound, M.P. 127 to 128 C.

Replacing the 2,3-dimethoxy-5,6,13,l3a-tetrahydro-8H- isoquino[1,2-b1quinazoline methiodide with 2,3-dibutyl- 5,6,13,13a tetrahydro 8H isoquino[l,2-b]quinazoline methiodide results in the preparation, in a similar manner, of the corresponding compound 1.

EXAMPLE 5 -chloro-2,3-dimethoxy-13-methyl-5,6,l3,13a-tetrahydro- 8H-isoquino[ 1,2-b1quinolin-8-one This example illustrates the preparation of a compound II, which is useful in preparing a compound III, as is illustrated in Example 6.

Heat under reflux a mixture of 50 parts of 6,7-dimethoxy-3,4-dihydroisoquinoline and 55 parts of 6-chloro-N- methyl isotoic anhydridein 500 parts by volume for 16 hours. Treat the mixture with carbon black and filter. Evaporate the filtrate under vacuum and crystallize the residue from methanol. Recrystallize the product from methylene chloride-methanol to obtain the title compound, M.P. 167 to 170 C.

Replacing the 6,7-methoxy-3,4-dihydroisoquino1ine with 6,7-diethoxy 3,4 dihydroxyisoquinoline results in the preparation, in a similar manner, of the corresponding compound II.

CHaO

CHaO- W EXAMPLE 6 10-chloro-2,3-dimethoxy-13-methyl-5,6, 13 l3a-tetrahydro 8H-isoquino[ 1,2-b] quinazoline CHa-N Add 30 parts of 10-chloro2,3-dimethoxy-13-methyl- 5 ,6, 13, 13a-tetrahydro-8H-isoquino 1,2-b quinazolin-8-one in 1500 parts by volume of ether to a refluxing solution of 9 parts of LAH in 1500 parts by volume of ether. Reflux the mixture for 18 hours. Cool the mixture and add 70 parts by volume of water. Filter the mixture and evaporate the filtrate under vacuum. Crystallize the residue from ether to obtain the title compound, M.P. 138 to 140 C.

Replacing the 10 chloro 2,3 dimethoxy-l3-methyl- 5,6,13,13 a-tetrahydro-SH-isoquino[1,2-b]quinazolin-8-one with 10,11-difluoro-2,3-dimethyl 13 methyl-5,6,13,13atetrahydro-8H-isoquino[1,2-b]quinazolin-8-one results in the preparation, in a similar manner, of the corresponding compound III.

EXAMPLE 7 10-chloro-13-methyl-5,6, 1 3,13 a-tetrahydro-8H-isoquino- [1,2-b] quinazolin-8 -one OHS-"IL F This example also illustrates the preparation of a compound II.

Reflux 29.5 parts of 3,4-dihydrosioquinoline and 32 parts of 6-ch10ro-N-methyl isotoic anhydride in 250 parts by volume of toluene for 18 hours. Treat the mixture with carbon black and filter. Evaporate the filtrate under vacuum and crystallize the resultant residue from ether to obtain the title compound, M.P. to 132 C.

Replacing the 6-chloro-N-methyl-isotoic anhydride with 5-butoxy-6-methyl-N-methyl-isotoic anhydride results in the preparation, in a similar manner, of the corresponding compound II.

EXAMPLE 8 5,6,13,13a-tetrahydro-8I-I-isoquino[1,2-b]quinolin-S-one This example also illustrates the preparation of a compound II.

Reflux under nitrogen for 16 hours a mixture of 19 parts of 3,4-dihydroisoquinoline and 21 parts of isotoic anhydride in 250 parts by volume of toluene. Treat the reaction mixture with carbon black and filter. Evaporate the filtrate under vacuum to obtain a residue, crystallize the residue from ether and recrystallize from benzene to obtain the title compound, M.P. 161 to 163 C.

Replacing the isotoic acid with 5,6-dipropylisotoic anhydride results in the preparation, in a similar manner, of the corresponding compound II.

EXAMPLE 9 2,3-dimethyl-13-methyl-5,6,8a,9,10,11,12,12a,13,l3 adecahydro8H-isoquino[ 1,2-b1quinazolin-8-one This example illustrates the preparation of a compound IId from a compound IIb.

Shake a solution of 18 parts of -chloro-2, 3-dimethoxy-l3-methyl-5,6,13,13a-tetrahydro-8H-isoquino[1,2 b] quinazolin-8-one in 150 parts by volume of glacial acetic acid containing 0.5 parts of PtO in an atmosphere of hydrogen (at 50 p.s.i.) for 20 hours. Filter the reaction mixture through Celite (diatomaceous earth) and evaporate the filtrate under vacuum. Mix the residue with sodium carbonate solution and methylene chloride, recover the methylene chloride layer and dry over sodium sulfate, then evaporate to obtain a residue. Crystallize the residue from ether to obtain the title compound, M.P. 146 to 148 C.

Replacing the 10-chloro-2,3-dimethoxy-13-methyl-5,6, 13,1Ba-tetrahydro-SH-isoquino[1,2-b]quinazolin 8 one with 2 propoxy-13-methyl-5,6,13,13a-tetrahydro-8H-isoquino[1,2-a]quinazolin-8-one results in the preparation, in a similar manner, of the corresponding compound IId.

EXAMPLE 10 10-chloro-2,3-dimethoxy-5,6-dihydro-8H-isoquino 1,2-b] quinazolin-S-one CHaO q CHsO 1 O This example illustrates the preparation of a compound VII.

Heat under reflux for 16 hours a mixture of 19 parts of 6,7-dimethoxy-3,4-dihydroisoquinoline and 17.5 parts of 6-chloro isotoic anhydride in 200 parts by volume of toluene. Treat the reaction mixture with carbon black and filter. Evaporate the filtrate under vacuum to a thick paste and triturate with 20 parts by volume of methanol and 100 parts by volume ether and filter to obtain the title compound, M.P. 255 to 257 C.

Replacing the 6,7-dimethoxy-3,4-dihydroisoquinoline With 6,7-dimethyl-3,4-dihydroisoquinoline results in the preparation, in a similar manner, of the corresponding compound VII.

12 EXAMPLE 11 CHaO CHsO

This example illustrates the preparation of a compound VIII.

Shake a solution of 1 part of 2,3-dimethoxy-5,6,13,13atetrahydro-8H-isoquino[1,2-b1quinazoline in parts by volume of ethanol, containing 0.2 parts of PtO in an atmosphere of hydrogen (50 p.s.i.) for 3 hours. Filter the reaction mixture through Celite and evaporate the filtrate under vacuum. Crystallize the residue twice from methanol to obtain the title compound, M.P. 156 to 159 C.

Replacing the 2,3-dimethoxy-5,6,13,13a-tetrahydro-8H- isoquino[l,2-b]quinazoline with 2-propoxy-5,6,13,l3atetrahydro-SH-isoquino[1,2-b]quinazoline results in the preparation, in a similar manner, of the corresponding compound VIII.

What is claimed is:

1. A compound of one of the formulae:

RLN

A1 II and R1 q R N I O N Al VII wherein:

Ring A is a member selected from the group consisting of ortho-phenylene and ortho-cyclohexylene;

R is a member selected from the group consisting of a hydrogen atom, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together With R methylenedioxy;

R is a member selected from the group consisting of a hydrogen atom, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms, and taken together with R methylenedioxy;

R is a member selected from the group consisting of a hydrogen atom and methyl;

A is a member selected from the group consisting of a hydrogen atom, fluoro, chloro, linear alkyl having from 1 to 4 carbon atoms, and, taken together with A methylenedioxy; and

13 A is a member selected from the group consisting of a hydrogen atom, fluoro, chloro, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with A methylenedioxy provided that each of A and A is a hydrogen atom where Ring A is orthocyclohexylene.

2. A compound according to claim 1 having the Formula II.

3. A compound according to claim 2 which is 2,3-dimethoxy 5,6,13,13a tetrahydro-8H isoquino[1,2 b] quinazolin-S-one.

4. A compound according to claim 2 which is 10- chloro 2,3 dimethoXy-l3-methyl-5,6,13-13a-tetrahydro- 8H-isoquino[1,2-b1quinazolin-8-one.

5. A compound according to claim 2 which is 10- chloro-13-methyl 5,6,13,13a tetrahydro-8H-isoquino[1, 2-b]quinaZolin-8-one.

6. A compound according to claim 2 which is 5,6,13, 13 a-tetrahydro-8H-isoquino 1,2-b] quinazolin-S-one.

14 7. A compound according to claim 2 which is 2,3- dimethoxy-l3-methyl-S,6,8a,9,10,.11,l2,l2a,13,l3a decahydro-8H-isoquino[1,2-b1quinazolin-8-one.

8. A compound according to claim 1 having the Formula VII.

9. A compound according to claim 8 which is 10- chloro 2,3-dimethoxy-5,6-dihydro-8H-isoquino[1,2 b] quinazolin-S-one.

References Cited Schopf et 211., CA. 42, 2602-3 (1948).

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R. 424-251 

